’s syndrome heterozygotes in Japan

Werner’s syndrome is an autosomal recessive disease that causes premature ageing accompanied by an increased susceptibility to cancer. The causative gene (W R N) codes for a DNA helicase. Worldwide, 1200 patients have been reported from 1904 to 1996; 845 from Japan. Patients are distributed all over Japan. But how widely distributed is the mutated WRN gene in the general population? We previously analysed the mutation in 63 patients with Werner’s syndrome, and found that among 126 chromosomes, 65 (51·6%) chromosomes had mutation 4 and 22 (17·5%) had mutation 6, and the rest had other mutations. We focused on mutations 4 and 6. DNA extracted from the blood of 1000 apparently healthy, unlinked anonymous volunteers in Kanagawa prefecture of Japan were analysed for mutations 4 and 6 by a method developed by us. Kanagawa prefecture is near Tokyo with a very mobile population and is considered to be a mix from various parts of Japan, like Tokyo. Mutation of positive DNAs was confirmed by the sequence of the PCR products around the mutation s i t e s . In these volunteers, we found six DNA samples with mutation 4 at one allele alone, but none with mutation 6. The prevalence of heterozygotic carriers with any one of the mutations 4 or 6 of W R N was estimated to be six per 1000 (95% exact mid-p CI: 2·4 to 12·5). If the other mutations of W R N in patients with Werner’s syndrome were considered, the prevalence of heterozygotic carriers is expected to be higher than six per 1000. This figure predicts more than 748 0 0 0 heterozygous carriers in the population of 124 7 09 000 in Japan (1996). From his result and the average birth rate between 1987 and 1996, we concluded that more than 23 babies with W R N mutations at both alleles are born each year. Cells from patients with Werner’s syndrome are genetically unstable and more senstive to genotoxic reagents, such as 4-nitroquinoline-1-oxide (4NQO) and camptothecin, than cells from unaffected individuals. 4NQO produces its cytotoxic effects more strongly in cells with a W R N m u t a t i o n at one allele than in the cells without a mutation. Because in Japan there may be nearly one million heterozygots, such people may have to be careful with drugs and chemicals, such as camptothecin used as an anticancer drug. We need to find out if heterozygotes are liable to any disease related to Werner’s syndrome, including cancers and diabetes.